RESUMO
BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear. METHODS: We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH. RESULTS: Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity. CONCLUSIONS: In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. (Funded by Eli Lilly; SYNERGY-NASH ClinicalTrials.gov number, NCT04166773.).
Assuntos
Cirrose Hepática , Humanos , Masculino , Cirrose Hepática/tratamento farmacológico , Feminino , Método Duplo-Cego , Pessoa de Meia-Idade , Adulto , Fígado/patologia , Fígado/efeitos dos fármacos , Fígado Gorduroso/tratamento farmacológico , Relação Dose-Resposta a Droga , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Injeções Subcutâneas , Idoso , Receptor do Peptídeo Semelhante ao Glucagon 2 , Polipeptídeo Inibidor GástricoRESUMO
BACKGROUND: Retatrutide (LY3437943) is an agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and glucagon receptors. Its dose-response relationships with respect to side effects, safety, and efficacy for the treatment of obesity are not known. METHODS: We conducted a phase 2, double-blind, randomized, placebo-controlled trial involving adults who had a body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) of 30 or higher or who had a BMI of 27 to less than 30 plus at least one weight-related condition. Participants were randomly assigned in a 2:1:1:1:1:2:2 ratio to receive subcutaneous retatrutide (1 mg, 4 mg [initial dose, 2 mg], 4 mg [initial dose, 4 mg], 8 mg [initial dose, 2 mg], 8 mg [initial dose, 4 mg], or 12 mg [initial dose, 2 mg]) or placebo once weekly for 48 weeks. The primary end point was the percentage change in body weight from baseline to 24 weeks. Secondary end points included the percentage change in body weight from baseline to 48 weeks and a weight reduction of 5% or more, 10% or more, or 15% or more. Safety was also assessed. RESULTS: We enrolled 338 adults, 51.8% of whom were men. The least-squares mean percentage change in body weight at 24 weeks in the retatrutide groups was -7.2% in the 1-mg group, -12.9% in the combined 4-mg group, -17.3% in the combined 8-mg group, and -17.5% in the 12-mg group, as compared with -1.6% in the placebo group. At 48 weeks, the least-squares mean percentage change in the retatrutide groups was -8.7% in the 1-mg group, -17.1% in the combined 4-mg group, -22.8% in the combined 8-mg group, and -24.2% in the 12-mg group, as compared with -2.1% in the placebo group. At 48 weeks, a weight reduction of 5% or more, 10% or more, and 15% or more had occurred in 92%, 75%, and 60%, respectively, of the participants who received 4 mg of retatrutide; 100%, 91%, and 75% of those who received 8 mg; 100%, 93%, and 83% of those who received 12 mg; and 27%, 9%, and 2% of those who received placebo. The most common adverse events in the retatrutide groups were gastrointestinal; these events were dose-related, were mostly mild to moderate in severity, and were partially mitigated with a lower starting dose (2 mg vs. 4 mg). Dose-dependent increases in heart rate peaked at 24 weeks and declined thereafter. CONCLUSIONS: In adults with obesity, retatrutide treatment for 48 weeks resulted in substantial reductions in body weight. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT04881760.).
Assuntos
Fármacos Antiobesidade , Polipeptídeo Inibidor Gástrico , Peptídeo 1 Semelhante ao Glucagon , Obesidade , Receptores de Glucagon , Adulto , Feminino , Humanos , Masculino , Índice de Massa Corporal , Método Duplo-Cego , Peptídeo 1 Semelhante ao Glucagon/agonistas , Obesidade/complicações , Obesidade/tratamento farmacológico , Resultado do Tratamento , Redução de Peso/efeitos dos fármacos , Polipeptídeo Inibidor Gástrico/agonistas , Receptores de Glucagon/agonistas , Injeções Subcutâneas , Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/efeitos adversos , Fármacos Antiobesidade/farmacologia , Fármacos Antiobesidade/uso terapêuticoRESUMO
BACKGROUND: According to current consensus guidelines for type 2 diabetes management, bodyweight management is as important as attaining glycaemic targets. Retatrutide, a single peptide with agonist activity at the glucose-dependent insulinotropic polypeptide (GIP), GLP-1, and glucagon receptors, showed clinically meaningful glucose-lowering and bodyweight-lowering efficacy in a phase 1 study. We aimed to examine the efficacy and safety of retatrutide in people with type 2 diabetes across a range of doses. METHODS: In this randomised, double-blind, double-dummy, placebo-controlled and active comparator-controlled, parallel-group, phase 2 trial, participants were recruited from 42 research and health-care centres in the USA. Adults aged 18-75 years with type 2 diabetes, glycated haemoglobin (HbA1c) of 7·0-10·5% (53·0-91·3 mmol/mol), and BMI of 25-50 kg/m2 were eligible for enrolment. Eligible participants were treated with diet and exercise alone or with a stable dose of metformin (≥1000 mg once daily) for at least 3 months before the screening visit. Participants were randomly assigned (2:2:2:1:1:1:1:2) using an interactive web-response system, with stratification for baseline HbA1c and BMI, to receive once-weekly injections of placebo, 1·5 mg dulaglutide, or retatrutide maintenance doses of 0·5 mg, 4 mg (starting dose 2 mg), 4 mg (no escalation), 8 mg (starting dose 2 mg), 8 mg (starting dose 4 mg), or 12 mg (starting dose 2 mg). Participants, study site personnel, and investigators were masked to treatment allocation until after study end. The primary endpoint was change in HbA1c from baseline to 24 weeks, and secondary endpoints included change in HbA1c and bodyweight at 36 weeks. Efficacy was analysed in all randomly assigned, except inadvertently enrolled, participants, and safety was assessed in all participants who received at least one dose of study treatment. The study is registered at ClinicalTrials.gov, NCT04867785. FINDINGS: Between May 13, 2021, and June 13, 2022, 281 participants (mean age 56·2 years [SD 9·7], mean duration of diabetes 8·1 years [7·0], 156 [56%] female, and 235 [84%] White) were randomly assigned and included in the safety analysis (45 in the placebo group, 46 in the 1·5 mg dulaglutide group, and 47 in the retatrutide 0·5 mg group, 23 in the 4 mg escalation group, 24 in the 4 mg group, 26 in the 8 mg slow escalation group, 24 in the 8 mg fast escalation group, and 46 in the 12 mg escalation group). 275 participants were included in the efficacy analyses (one each in the retatrutide 0·5 mg group, 4 mg escalation group, and 8 mg slow escalation group, and three in the 12 mg escalation group were inadvertently enrolled). 237 (84%) participants completed the study and 222 (79%) completed study treatment. At 24 weeks, least-squares mean changes from baseline in HbA1c with retatrutide were -0·43% (SE 0·20; -4·68 mmol/mol [2·15]) for the 0·5 mg group, -1·39% (0·14; -15·24 mmol/mol [1·56]) for the 4 mg escalation group, -1·30% (0·22; -14·20 mmol/mol [2·44]) for the 4 mg group, -1·99% (0·15; -21·78 mmol/mol [1·60]) for the 8 mg slow escalation group, -1·88% (0·21; -20·52 mmol/mol [2·34]) for the 8 mg fast escalation group, and -2·02% (0·11; -22·07 mmol/mol [1·21]) for the 12 mg escalation group, versus -0·01% (0·21; -0·12 mmol/mol [2·27]) for the placebo group and -1·41% (0·12; -15·40 mmol/mol [1·29]) for the 1·5 mg dulaglutide group. HbA1c reductions with retatrutide were significantly greater (p<0·0001) than placebo in all but the 0·5 mg group and greater than 1·5 mg dulaglutide in the 8 mg slow escalation group (p=0·0019) and 12 mg escalation group (p=0·0002). Findings were consistent at 36 weeks. Bodyweight decreased dose dependently with retatrutide at 36 weeks by 3·19% (SE 0·61) for the 0·5 mg group, 7·92% (1·28) for the 4 mg escalation group, 10·37% (1·56) for the 4 mg group, 16·81% (1·59) for the 8 mg slow escalation group, 16·34% (1·65) for the 8 mg fast escalation group, and 16·94% (1·30) for the 12 mg escalation group, versus 3·00% (0·86) with placebo and 2·02% (0·72) with 1·5 mg dulaglutide. For retatrutide doses of 4 mg and greater, decreases in weight were significantly greater than with placebo (p=0·0017 for the 4 mg escalation group and p<0·0001 for others) and 1·5 mg dulaglutide (all p<0·0001). Mild-to-moderate gastrointestinal adverse events, including nausea, diarrhoea, vomiting, and constipation, were reported in 67 (35%) of 190 participants in the retatrutide groups (from six [13%] of 47 in the 0·5 mg group to 12 [50%] of 24 in the 8 mg fast escalation group), six (13%) of 45 participants in the placebo group, and 16 (35%) of 46 participants in the 1·5 mg dulaglutide group. There were no reports of severe hypoglycaemia and no deaths during the study. INTERPRETATION: In people with type 2 diabetes, retatrutide showed clinically meaningful improvements in glycaemic control and robust reductions in bodyweight, with a safety profile consistent with GLP-1 receptor agonists and GIP and GLP-1 receptor agonists. These phase 2 data also informed dose selection for the phase 3 programme. FUNDING: Eli Lilly and Company.
Assuntos
Diabetes Mellitus Tipo 2 , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Método Duplo-Cego , Glucagon/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon , Receptor do Peptídeo Semelhante ao Glucagon 1/uso terapêutico , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Glucose , Hipoglicemiantes/efeitos adversos , Receptores de Glucagon/uso terapêutico , Resultado do Tratamento , Adolescente , Adulto Jovem , IdosoRESUMO
We investigated non-alcoholic fatty liver disease (NAFLD) prevalence and its metabolic associations in patients with type 1 diabetes (T1D), and in insulin-naïve and insulin-treated patients with type 2 diabetes (T2D). Baseline data from patients who had liver fat content (LFC) evaluated by magnetic resonance imaging in four phase 3 studies of basal insulin peglispro (BIL) were analysed. Associations of NAFLD with clinical characteristics, glycaemic control and diabetes therapy were evaluated. The prevalence of NAFLD (defined as LFC ≥ 6%) was low in T1D (8.8%) but high in T2D, with greater prevalence in insulin-naïve (75.6%) vs insulin-treated (61.7%) T2D patients. LFC (mean ± SD) was higher in T2D patients (insulin-naïve, 13.0% ± 8.4%; insulin-treated, 10.2% ± 7.8%) than in T1D patients (3.2% ± 3.2%). In T2D, NAFLD was associated with several markers of insulin resistance. In all three populations, there was an absence of association of HbA1c with LFC, but insulin doses were higher in patients with NAFLD.
Assuntos
Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/metabolismo , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Adulto , Idoso , Ensaios Clínicos Fase III como Assunto/estatística & dados numéricos , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/análogos & derivados , Insulina/uso terapêutico , Insulina Lispro/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Polietilenoglicóis/uso terapêutico , Prevalência , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Estudos RetrospectivosRESUMO
Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is the most common form of chronic liver disease. It exists as either simple steatosis or its more progressive form, metabolic dysfunction-associated steatohepatitis (MASH), formerly, non-alcoholic steatohepatitis (NASH). The global prevalence of MASLD is estimated to be 32% among adults and is projected to continue to rise with increasing rates of obesity, type 2 diabetes, and metabolic syndrome. While simple steatosis is often considered benign and reversible, MASH is progressive, potentially leading to the development of cirrhosis, liver failure, and hepatocellular carcinoma. Treatment of MASH is therefore directed at slowing, stopping, or reversing the progression of disease. Evidence points to improved liver histology with therapies that result in sustained body weight reduction. Incretin-based molecules, such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs), alone or in combination with glucose-dependent insulinotropic polypeptide (GIP) and/or glucagon receptor agonists, have shown benefit here, and several are under investigation for MASLD/MASH treatment. In this review, we discuss current published data on GLP-1, GIP/GLP-1, GLP-1/glucagon, and GLP-1/GIP/glucagon RAs in MASLD/MASH, focusing on their efficacy on liver histology, liver fat, and MASH biomarkers.
Assuntos
Incretinas , Hepatopatia Gordurosa não Alcoólica , Humanos , Incretinas/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Diabetes Mellitus Tipo 2/tratamento farmacológicoRESUMO
BACKGROUND: The use of histological inclusion criteria for clinical trials of at-risk metabolic dysfunction-associated steatohepatitis (MASH) is often associated with high screen failure rates. AIMS: To describe the design of a trial investigating tirzepatide treatment of MASH and to examine the effect of new inclusion criteria incorporating the use of the FibroScan-AST (FAST) score on the proportion of patients meeting histological criteria. METHODS: SYNERGY-NASH is a Phase 2b, multicentre, randomised, double-blinded, placebo-controlled trial in patients with biopsy-confirmed MASH, F2-F3 fibrosis and NAFLD Activity Score ≥4. New inclusion criteria (FAST score >0.35 and an increase in AST inclusion criterion from >20 to >23 U/L) were adopted during the trial, allowing us to examine its impact on the qualification rate. RESULTS: 1583 participants were screened, 651 participants proceeded to liver biopsy and 190 participants were randomised with an overall screen fail rate of 87%. Following the protocol amendment, the overall qualification rate for per-protocol biopsies was minimally changed from 27.5% to 28.9% with considerable variation among different investigator medical speciality types: endocrinology: from 37.5% to 39.3%; gastroenterology/hepatology: from 26.0% to 23.3%; other specialities: from 21.3% to 29.7%. At 29 sites that performed per-protocol biopsies before and after the amendment, qualification rates changed as follows: all: 26.1% to 29.1%; endocrinology: from 35.0% to 40.9%; gastroenterology/hepatology: 25.6% to 20.0%; other specialities: from 16.1% to 27.8%. CONCLUSIONS: For at-risk MASH trials based on liver histology, the implementation of inclusion criteria with the proposed FAST score and AST cut-offs in this trial was most effective at non-specialist sites.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Humanos , Método Duplo-Cego , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Biópsia/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Fígado/efeitos dos fármacos , Fígado/metabolismo , Seleção de PacientesRESUMO
Retatrutide is a novel triple agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1 and glucagon receptors. A 48-week phase 2 obesity study demonstrated weight reductions of 22.8% and 24.2% with retatrutide 8 and 12 mg, respectively. The primary objective of this substudy was to assess mean relative change from baseline in liver fat (LF) at 24 weeks in participants from that study with metabolic dysfunction-associated steatotic liver disease and ≥10% of LF. Here, in this randomized, double-blind, placebo-controlled trial, participants (n = 98) were randomly assigned to 48 weeks of once-weekly subcutaneous retatrutide (1, 4, 8 or 12 mg dose) or placebo. The mean relative change from baseline in LF at 24 weeks was -42.9% (1 mg), -57.0% (4 mg), -81.4% (8 mg), -82.4% (12 mg) and +0.3% (placebo) (all P < 0.001 versus placebo). At 24 weeks, normal LF (<5%) was achieved by 27% (1 mg), 52% (4 mg), 79% (8 mg), 86% (12 mg) and 0% (placebo) of participants. LF reductions were significantly related to changes in body weight, abdominal fat and metabolic measures associated with improved insulin sensitivity and lipid metabolism. The ClinicalTrials.gov registration is NCT04881760 .
Assuntos
Fígado Gorduroso , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Fígado Gorduroso/tratamento farmacológico , Adulto , Método Duplo-Cego , Receptores de Glucagon/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Fígado/efeitos dos fármacos , Fígado/metabolismo , Obesidade/tratamento farmacológico , Obesidade/complicações , Idoso , Ácidos Graxos , PeptídeosRESUMO
OBJECTIVE: The effects of GH replacement on glucose metabolism in GH-deficient (GHD) adults in clinical practice are not well defined. Therefore, we assessed GH treatment effects on fasting plasma glucose (FPG) and haemoglobin A1c (A1c) concentrations in GHD adults in a clinical setting. DESIGN: Post-hoc analysis of the observational Hypopituitary Control and Complications Study conducted at 157 US centres (1997-2002). PATIENTS: GH-deficient adults who were GH-naïve at study entry and had at least two FPG measurements. MEASUREMENTS: Effect of GH treatment on the frequency and time course of abnormal FPG (> or =5.6 mmol/l) development, FPG normalization, progression of increased FPG and abnormal follow-up A1c (>6%) values in GHD patients treated with GH (n = 403) or untreated (n = 169) at their physician's discretion. RESULTS: In subjects without pre-existing diabetes mellitus, development of an abnormal FPG tended to occur in a greater percentage of GH-treated than untreated subjects (35.3% versus 24.5, P = 0.06). Additionally, GH treatment was associated with a mild, transient increase in FPG and shorter time to development of an abnormal FPG in these subjects (P < 0.01). Most ( approximately 80%) abnormal FPG values were below 7 mmol/l and normalized in 69% of GH-treated subjects without diabetes. Treatment with GH had no effect on the rate of FPG normalization, progression of increased FPG or abnormal follow-up A1c values. CONCLUSIONS: Initiation of GH replacement in GHD adults was associated with a mild increase in FPG that often normalized spontaneously. Nevertheless, clinicians should monitor FPG in patients receiving GH treatment.
Assuntos
Intolerância à Glucose/epidemiologia , Transtornos do Crescimento/tratamento farmacológico , Transtornos do Crescimento/epidemiologia , Hormônio do Crescimento Humano/uso terapêutico , Adulto , Algoritmos , Glicemia/metabolismo , Complicações do Diabetes/sangue , Complicações do Diabetes/tratamento farmacológico , Complicações do Diabetes/metabolismo , Jejum/sangue , Jejum/metabolismo , Seguimentos , Hemoglobinas Glicadas/análise , Transtornos do Crescimento/sangue , Transtornos do Crescimento/metabolismo , Terapia de Reposição Hormonal/efeitos adversos , Terapia de Reposição Hormonal/estatística & dados numéricos , Hormônio do Crescimento Humano/efeitos adversos , Hormônio do Crescimento Humano/deficiência , Humanos , Incidência , Pessoa de Meia-Idade , Fatores de TempoRESUMO
OBJECTIVE: To determine the effect of tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 receptors, on biomarkers of nonalcoholic steatohepatitis (NASH) and fibrosis in patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: Patients with T2DM received either once weekly tirzepatide (1, 5, 10, or 15 mg), dulaglutide (1.5 mg), or placebo for 26 weeks. Changes from baseline in alanine aminotransferase (ALT), aspartate aminotransferase (AST), keratin-18 (K-18), procollagen III (Pro-C3), and adiponectin were analyzed in a modified intention-to-treat population. RESULTS: Significant (P < 0.05) reductions from baseline in ALT (all groups), AST (all groups except tirzepatide 10 mg), K-18 (tirzepatide 5, 10, 15 mg), and Pro-C3 (tirzepatide 15 mg) were observed at 26 weeks. Decreases with tirzepatide were significant compared with placebo for K-18 (10 mg) and Pro-C3 (15 mg) and with dulaglutide for ALT (10, 15 mg). Adiponectin significantly increased from baseline with tirzepatide compared with placebo (10, 15 mg). CONCLUSIONS: In post hoc analyses, higher tirzepatide doses significantly decreased NASH-related biomarkers and increased adiponectin in patients with T2DM.
Assuntos
Biomarcadores/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Polipeptídeo Inibidor Gástrico/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Adulto , Alanina Transaminase/metabolismo , Aspartato Aminotransferases/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Polipeptídeo Inibidor Gástrico/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Humanos , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptores dos Hormônios Gastrointestinais/agonistas , Proteínas Recombinantes de Fusão/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: GH therapy in adult patients with GH deficiency (GHD) was approved over 10 yr ago, and the indication has subsequently gained broad acceptance. The HypoCCS surveillance database is a suitable means to examine the evolution of diagnostic patterns since 1996. METHODS: Baseline demographics, reported cause of GHD, and diagnostic tests were available from 5893 GH-treated patients. Trends for change over time in diagnosis, GH stimulation test data, and IGF-I measurements were analyzed at 2-yr intervals by linear regression models, with entry year as the predictive variable. RESULTS: Over the decade, there was a decrease in patients enrolled with diagnoses of pituitary adenoma (50.2 to 38.6%; P < 0.001), craniopharyngioma (13.3 to 8.4%; P = 0.005) and pituitary hemorrhage (5.8 to 2.8%; P = 0.001); increases in idiopathic GHD (13.9 to 19.3%; P < 0.001), less common diagnoses (7.4 to 15.8%; P < 0.001), and undefined/unknown diagnoses (1.3 to 8.6%; P < 0.001) were observed. Use of arginine, clonidine, and L-dopa tests declined, whereas use of the GHRH-arginine test increased. Median values for peak GH from all tests except GHRH-arginine and for IGF-I SD scores increased significantly (P < 0.001). Over the decade (1996--2005), idiopathic GHD was reported for 16.7% of patients, and more than half of these had adult onset GHD. In the idiopathic adult onset group, 40.2% had isolated GHD; 18.3 and 4.4% had a stimulation test GH peak of at least 3.0 and 5.0 microg/liter, respectively. CONCLUSIONS: Significant shifts in diagnostic patterns have occurred since approval of the adult GHD indication, with a trend to less severe forms of GHD.
Assuntos
Bases de Dados Factuais , Transtornos do Crescimento/diagnóstico , Hormônio do Crescimento Humano/deficiência , Vigilância da População , Prática Profissional/tendências , Adulto , Idade de Início , Arginina/análise , Técnicas de Diagnóstico Endócrino/tendências , Feminino , Transtornos do Crescimento/classificação , Transtornos do Crescimento/epidemiologia , Transtornos do Crescimento/etiologia , Hormônio Liberador de Hormônio do Crescimento/análise , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Resistência à Insulina/fisiologia , Masculino , Pessoa de Meia-Idade , Doenças da Hipófise/complicações , Doenças da Hipófise/diagnóstico , Vigilância da População/métodosRESUMO
CONTEXT: Several studies have demonstrated an improvement in aerobic exercise capacity with 6 months of GH replacement in adults with GH deficiency (GHD). OBJECTIVE: The objective of the study was to determine whether improvements in aerobic exercise capacity with GH treatment in adults with GHD are related to changes in physical activity or affected by the GH dosing regimen. DESIGN: This was a randomized, two-arm, parallel, open-label study. SETTING: The study was conducted at five academic medical centers with exercise physiology laboratories. SUBJECTS: Study subjects were adults (n = 29) with GHD due to hypothalamic-pituitary disease. INTERVENTIONS: The intervention was GH replacement therapy, administered either as a fixed body weight-based dosing regimen as an individualized dose titration regimen for 32 wk. MAIN OUTCOME MEASURES: Maximal oxygen consumption (VO2 max) and oxygen consumption (VO2) at the lactate threshold, ventilatory threshold using a cycle ergometry protocol, and weekly energy expenditure (physical activity questionnaire), assessed at baseline and end point, were measured. RESULTS: In the group as a whole, VO2 max increased significantly (by 9%) from baseline (19.1+/- 0.89 ml/kg.min) to end point (21.6 +/- 1.23 ml/kg.min, P = 0.010). Compared with baseline, VO2 max also changed significantly within the individualized dose titration regimen group (+2.5 +/- 0.98 ml/kg.min, P =0.034) but not within the fixed body weight-based dosing regimen group (+1.2 +/- 0.78 ml/kg.min, P = 0.15), although these changes from baseline were not significantly different between the two groups. VO2 at lactate threshold, VO2 at ventilatory threshold, and weekly energy expenditure also did not change. CONCLUSIONS: GH replacement therapy in GH-deficient adults improved VO2 max similarly with both dosing regimens, without any influence of physical activity. There was no effect on submaximal exercise performance.
Assuntos
Exercício Físico/fisiologia , Terapia de Reposição Hormonal/métodos , Hormônio do Crescimento Humano/administração & dosagem , Hormônio do Crescimento Humano/deficiência , Consumo de Oxigênio/efeitos dos fármacos , Adulto , Gasometria , Teste de Esforço , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Lactatos/sangue , Pessoa de Meia-Idade , Consumo de Oxigênio/fisiologia , Estatísticas não Paramétricas , Inquéritos e QuestionáriosRESUMO
Data on cytokeratin-18 (K-18) and enhanced liver fibrosis (ELF) score in insulin-treated diabetes patients with non-alcoholic fatty liver disease (NAFLD) are limited. This study analyzed phase III data comparing basal insulin peglispro (BIL) and insulin glargine in type 1 (T1D), and type 2 diabetes (T2D) (insulin-naïve and insulin-treated). Alanine aminotransferase (ALT), K-18, ELF scores and liver fat content (LFC), measured by MRI, were obtained longitudinally. Baseline K-18 (U/L) was higher in T2D (range: 207â247) than T1D (range: 148â183), correlated with ALT in all populations (r (range) 0.264â0.637, p<0.05), but with LFC only in T2D (r (range) 0.474â0.586, p<0.05). K-18 increased significantly from baseline in BIL-treated, but not glargine-treated patients. Change from baseline (CFB) K-18 was significantly correlated with CFB in ALT in BIL-treated T2D populations. Baseline ELF scores were higher in T2D (range: 9.12â9.20) than T1D (range: 8.24â8.36), correlated with ALT in T1D only (0.209, p<0.05), and not correlated with LFC in any population. ELF scores increased significantly from baseline in BIL-treated but not glargine-treated patients. There were no correlations between CFB in LFC and ELF score at week 52 in any treatment group/population. In all BIL-treated populations, CFB in ALT and CFB in ELF score at week 52 were positively correlated. These data characterize associations of K-18 and ELF score with ALT and LFC in insulin-treated patients with T1D and T2D. Hepatopreferential insulins may be associated with increased K-18 and ELF scores but mechanisms and clinical significance are unknown. ClinicalTrials.gov identifiers are NCT01481779, NCT01435616, NCT01454284 and NCT01582451.
Assuntos
Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insulina/uso terapêutico , Queratina-18/sangue , Cirrose Hepática/sangue , Adiposidade , Adulto , Demografia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Cirrose Hepática/complicações , MasculinoRESUMO
UNLABELLED: To determine if replacement of GH improves BMD in adult-onset GHD, we administered GH in physiologic amounts to men and women with GHD. GH replacement significantly increased spine BMD in the men by 3.8%. INTRODUCTION: Growth hormone (GH) deficiency (GHD) acquired in adulthood results in diminished BMD; the evidence that replacement of GH improves BMD is not conclusive. We therefore performed a randomized, placebo-controlled trial to determine whether GH replacement would increase lumbar spine BMD in a combined group of men and women with adult-onset GHD. MATERIALS AND METHODS: We randomized 67 men and women to receive GH (n=33) or placebo (n=34) for 2 yr. The GH dose was initially 2 microg/kg body weight/d, increased gradually to a maximum of 12 microg/kg/d and adjusted to maintain a normal IGF-I concentration for age and sex. BMD was assessed before treatment and at 6, 12, 18, and 24 mo of treatment. Fifty-four subjects completed the protocol. RESULTS: BMD of the lumbar spine in the entire group increased by 2.9 +/- 3.9% above baseline in the GH-treated subjects, which was significantly (p=0.037) greater than the 1.4 +/- 4.5% increase in the placebo-treated subjects. In a secondary analysis, spine BMD in GH-treated men increased 3.8 +/- 4.3% above baseline, which was significantly (p=0.001) greater than that in placebo-treated men (0.4 +/- 4.7%), but the change in GH-treated women was not significantly different from that in placebo-treated women. Treatment with GH did not increase total hip BMD more than placebo treatment after 2 yr. CONCLUSIONS: We conclude that GH replacement in men who have adult-onset GHD improves their spine BMD, but we cannot draw any conclusions about the effect of GH replacement on spine BMD in women with adult-onset GHD.
Assuntos
Densidade Óssea/efeitos dos fármacos , Hormônio do Crescimento/deficiência , Hormônio do Crescimento/uso terapêutico , Terapia de Reposição Hormonal , Vértebras Lombares , Adulto , Biomarcadores/metabolismo , Relação Dose-Resposta a Droga , Feminino , Humanos , Hipopituitarismo/complicações , Hipopituitarismo/tratamento farmacológico , Vértebras Lombares/metabolismo , Masculino , Pessoa de Meia-Idade , Fatores SexuaisRESUMO
OBJECTIVE: To evaluate the efficacy and safety of basal insulin peglispro (BIL) versus insulin glargine in patients with type 2 diabetes (hemoglobin A1c [HbA1c] ≤9% [75 mmol/mol]) treated with basal insulin alone or with three or fewer oral antihyperglycemic medications. RESEARCH DESIGN AND METHODS: This 52-week, open-label, treat-to-target study randomized patients (mean HbA1c 7.42% [57.6 mmol/mol]) to BIL (n = 307) or glargine (n = 159). The primary end point was change from baseline HbA1c to 26 weeks (0.4% [4.4 mmol/mol] noninferiority margin). RESULTS: At 26 weeks, reduction in HbA1c was superior with BIL versus glargine (-0.82% [-8.9 mmol/mol] vs. -0.29% [-3.2 mmol/mol]; least squares mean difference -0.52%, 95% CI -0.67 to -0.38 [-5.7 mmol/mol, 95% CI -7.3 to -4.2; P < 0.001); greater reduction in HbA1c with BIL was maintained at 52 weeks. More BIL patients achieved HbA1c <7% (53 mmol/mol) at weeks 26 and 52 (P < 0.001). With BIL versus glargine, nocturnal hypoglycemia rate was 60% lower, more patients achieved HbA1c <7% (53 mmol/mol) without nocturnal hypoglycemia at 26 and 52 weeks (P < 0.001), and total hypoglycemia rates were lower at 52 weeks (P = 0.03). At weeks 26 and 52, glucose variability was lower (P < 0.01), basal insulin dose was higher (P < 0.001), and triglycerides and aminotransferases were higher with BIL versus glargine (P < 0.05). Liver fat content (LFC), assessed in a subset of patients (n = 162), increased from baseline with BIL versus glargine (P < 0.001), with stable levels between 26 and 52 weeks. CONCLUSIONS: BIL provided superior glycemic control versus glargine, with reduced nocturnal and total hypoglycemia, lower glucose variability, and increased triglycerides, aminotransferases, and LFC.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina Glargina/uso terapêutico , Insulina Lispro/uso terapêutico , Idoso , Glicemia , Feminino , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemia/induzido quimicamente , Masculino , Pessoa de Meia-IdadeRESUMO
To determine whether an individualized dose titration regimen (ID) for adult GH replacement therapy would have similar efficacy and better tolerability than a fixed body weight-based dosing regimen (FD), 387 adults with GH deficiency were randomized to FD (n = 200) or ID (n = 187) for 32 wk. In FD, subjects received sequentially 4, 8, and 12 microg/kg.d GH. ID was started at 0.2 mg/d and increased by 0.2-mg/d increments, based on clinical and serum IGF-I responses, to a maximum of 0.8 mg/d. Increases (mean +/- sd) in serum IGF-I were similar in both groups (FD, 110.2 +/- 87.8 vs. ID, 99.6 +/- 77.7 microg/liter, P = 0.20) despite higher final GH doses in FD (0.70 +/- 0.32 vs. 0.54 +/- 0.22 mg/d, P < 0.001). Favorable changes in several efficacy measures were observed with no significant differences between the FD and ID groups: lean body mass increased; health-related quality of life improved; and abdominal fat mass, hip circumference, sum of skinfolds, and total and low-density lipoprotein cholesterol decreased. The decrease in fat mass was greater with FD than ID for men (-2.7 +/- 2.7 kg vs. -1.8 +/- 2.5 kg, P = 0.04) but not for women (-2.1 +/- 2.4 vs. -2.0 +/- 3.8 kg). The change in waist circumference was greater with FD than ID for women but not for men. There was a significant reduction of systolic blood pressure in ID but not in FD. The adverse event profile was similar between FD and ID except that ID had a lower occurrence of peripheral edema (9.1% vs. 16.5%, P = 0.03) and rash (1.1% vs. 5.5%, P = 0.02) than FD. In summary, the use of ID resulted in improved tolerability and similar efficacy compared with FD. We conclude that GH replacement therapy should be initiated at a low dose and titrated to a dose producing maximal benefits without adverse side effects and an IGF-I level within the age- and sex-adjusted normal range.
Assuntos
Peso Corporal , Terapia de Reposição Hormonal , Hormônio do Crescimento Humano/administração & dosagem , Hormônio do Crescimento Humano/efeitos adversos , Fator de Crescimento Insulin-Like I/metabolismo , Adulto , Relação Dose-Resposta a Droga , Feminino , Terapia de Reposição Hormonal/efeitos adversos , Hormônio do Crescimento Humano/deficiência , Humanos , Masculino , Erros Inatos do Metabolismo/tratamento farmacológico , Erros Inatos do Metabolismo/fisiopatologia , Pessoa de Meia-Idade , Qualidade de Vida , Inquéritos e Questionários , Resultado do TratamentoRESUMO
Adult GH deficiency (GHD) is currently diagnosed in patients with either a history of childhood-onset GHD or acquired hypothalamic-pituitary disease by GH stimulation testing. However, GH stimulation tests are invasive, time consuming, and associated with side effects. Based on preliminary analyses of patients enrolled in the U.S. Hypopituitary Control and Complications Study (HypoCCS), we proposed the presence of adult GHD could be predicted with 95% accuracy by the presence of three or more pituitary hormone deficiencies (PHDs) or a serum IGF-I concentration less than 84 microg/liter (11 nmol/liter). To validate the diagnostic utility of these criteria, we studied results obtained in 817 adult patients (mean [SD] age: 46.4 [15.7] yr, body mass index: 30.1 [7.2] kg/m(2)) enrolled in HypoCCS who had serum GH concentrations from stimulation tests (11 different tests used, excluding clonidine) and serum IGF-I (competitive binding RIA) measured at the central laboratory (Esoterix Endocrinology, Calabasas Hills, CA). When patients were stratified into subgroups on the basis of the presence of zero, one, two, three, and four additional PHDs, median (25th, 75th percentile) peak GH levels (micrograms per liter) were 3.5 (0.85, 7.1), 0.73 (0.18, 4.2), 0.29 (0.05, 1.4), 0.06 (0.025, 0.295), and 0.025 (0.025, 0.07), respectively. The mean log (peak GH) concentration was significantly different among the subgroups (P < 0.05). The proportion of patients in each group with severe GHD diagnosed by stimulation testing (peak GH < 2.5 microg/liter) was 41%, 67%, 83%, 96%, and 99% for patients with zero, one, two, three, and four PHDs, respectively. The positive predictive values (PPVs) for GHD of three PHDs, four PHDs, and serum IGF-I less than 84 microg/liter were 96%, 99%, and 96%, respectively. The PPV of these three diagnostic criteria was also 95% or more after excluding the data originally used to identify these potential predictors. Taken together, the presence of either three or four additional PHDs or IGF-I less than 84 microg/liter (55% of the patients met at least one of these criteria) reliably predicted GHD with a high PPV (95%), high specificity (89%), and moderate sensitivity (69%). We concluded that patients with an appropriate clinical history and either the presence of three or four additional PHDs or serum IGF-I less than 84 microg/liter (measured in the Esoterix assay) do not require GH stimulation testing for the diagnosis of adult GHD. In clinical practice, we suggest that other causes of low serum IGF-I should be excluded before applying these diagnostic criteria.
Assuntos
Doenças do Sistema Endócrino/diagnóstico , Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/metabolismo , Adulto , Envelhecimento/metabolismo , Índice de Massa Corporal , Feminino , Hormônio do Crescimento Humano/sangue , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-Idade , Hormônios Hipofisários/deficiência , Valor Preditivo dos TestesRESUMO
Although the use of the insulin tolerance test (ITT) for the diagnosis of adult GH deficiency is well established, diagnostic peak GH cut-points for other commonly used GH stimulation tests are less clearly established. Despite that fact, the majority of patients in the United States who are evaluated for GH deficiency do not undergo insulin tolerance testing. The aim of this study was to evaluate the relative utility of six different methods of testing for adult GH deficiency currently used in practice in the United States and to develop diagnostic cut-points for each of these tests. Thirty-nine patients (26 male, 13 female) with adult-onset hypothalamic-pituitary disease and multiple pituitary hormone deficiencies were studied in comparison with age-, sex-, estrogen status-, and body mass index-matched control subjects (n = 34; 20 male, 14 female). A third group of patients (n = 21) with adult-onset hypothalamic-pituitary disease and no more than one additional pituitary hormone deficiency was also studied. The primary end-point was peak serum GH response to five GH stimulation tests administered in random order at five separate visits: ITT, arginine (ARG), levodopa (L-DOPA), ARG plus L-DOPA, and ARG plus GHRH. Serum IGF-I concentrations were also measured on two occasions. For purposes of analysis, patients with multiple pituitary hormone deficiencies were assumed to be GH deficient. Three diagnostic cut-points were calculated for each test to provide optimal separation of multiple pituitary hormone deficient and control subjects according to three criteria: 1) to minimize misclassification of control subjects and deficient patients (balance between high sensitivity and high specificity); 2) to provide 95% sensitivity for GH deficiency; and 3) to provide 95% specificity for GH deficiency. The greatest diagnostic accuracy occurred with the ITT and the ARG plus GHRH test, although patients preferred the latter (P = 0.001). Using peak serum GH cut-points of 5.1 microg/liter for the ITT and 4.1 microg/liter for the ARG plus GHRH test, high sensitivity (96 and 95%, respectively) and specificity (92 and 91%, respectively) for GH deficiency were achieved. To obtain 95% specificity, the peak serum GH cut-points were lower at 3.3 microg/liter and 1.5 microg/liter for the ITT and ARG plus GHRH test, respectively. There was substantial overlap between patients and control subjects for the ARG plus L-DOPA, ARG, and L-DOPA tests, but test-specific cut-points could be defined for all three tests to provide 95% sensitivity for GH deficiency (peak GH cut-points: 1.5, 1.4 and 0.64 microg/liter, respectively). However, 95% specificity could be achieved with the ARG plus L-DOPA and ARG tests only with very low peak GH cut-points (0.25 and 0.21 microg/liter, respectively) and not at all with the L-DOPA test. Although serum IGF-I levels provided less diagnostic discrimination than all five GH stimulation tests, a value below 77.2 microg/liter was 95% specific for GH deficiency. In conclusion, the diagnosis of adult GH deficiency can be made without performing an ITT, provided that test-specific cut-points are used. The ARG plus GHRH test represents an excellent alternative to the ITT for the diagnosis of GH deficiency in adults.
Assuntos
Técnicas de Diagnóstico Endócrino , Hormônio do Crescimento Humano/deficiência , Adulto , Idoso , Envelhecimento/sangue , Arginina , Índice de Massa Corporal , Combinação de Medicamentos , Feminino , Hormônio Liberador de Hormônio do Crescimento , Hormônio do Crescimento Humano/sangue , Humanos , Hipoglicemiantes , Insulina , Fator de Crescimento Insulin-Like I/análise , Levodopa , Masculino , Doenças Metabólicas/sangue , Doenças Metabólicas/diagnóstico , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Caracteres Sexuais , Estimulação QuímicaRESUMO
To develop reference ranges for the Questions on Life Satisfaction Hypopituitarism Module (QLS-H), a new quality of life questionnaire for patients with hypopituitarism, data from 8177 adults were collected in France, Germany, Italy, The Netherlands, Spain, the United Kingdom, and the United States QLS-H scores declined with age, were lower in females than males, and differed significantly among countries. From these reference ranges we derived equations for z-scores, which adjust for age, gender, and country. QLS-H results from 957 adults with GH deficiency (GHD) participating in clinical trials were analyzed. At baseline, QLS-H scores were lower in females and differed significantly among countries. QLS-H scores significantly increased after GH treatment (6-8 months), but differences by country persisted. Calculating z-scores for patients eliminated all gender and most country differences. Pooled z-scores (mean +/- SD) from all patients increased from -0.99 +/- 1.39 at baseline to -0.14 +/- 1.30 after GH treatment. Quality of life assessment in adults with GHD requires the use of z-scores to correct for age, gender, and country differences. This approach allows pooling of data from different cohorts and comparison with general populations. QLS-H scores in adults with GHD were significantly decreased at baseline and were almost normalized after 6-8 months of GH therapy.
Assuntos
Hormônio do Crescimento Humano/deficiência , Hipopituitarismo/psicologia , Qualidade de Vida , Adulto , Fatores Etários , Estudos de Coortes , Europa (Continente) , Feminino , Hormônio do Crescimento/uso terapêutico , Humanos , Masculino , Satisfação Pessoal , Valores de Referência , Fatores Sexuais , Inquéritos e QuestionáriosRESUMO
We examined the relationship between abdominal visceral fat (AVF) and plasma concentrations of lipids and lipoproteins in 19 females (F) (not on estrogen) and 31 males (M) over the age of 60 (age = 66.8 years). In addition, the effects of growth hormone (GH) release, fitness (Vo(2) peak), insulin, and glucose concentrations (both fasting and in response to an oral glucose tolerance test) on lipids were examined. Subjects were categorized by low (L) and high (H) AVF (L < 130 cm(2), H > 130 cm(2)), fat mass (FM) (above or below median value), and AVF corrected for fat mass. Factorial analysis of variance (ANOVA) showed that when subjects were divided by AVF and FM, similar results were observed with H > L (P <.05) for very-low-density lipoprotein-cholesterol (VLDL-C), triglycerides (TG), VLDL-TG, apolipoprotein (apo)-B, apo-B VLDL, cholesterol (Chol)/high-density lipoprotein (HDL), LDL/HDL, apoB/A1 and L > H for HDL, HDL(2), HDL(3), apo A1, and LDL/apo-B LDL. Gender differences were also observed with F > M for Chol, LDL, HDL, and HDL(2). When AVF was corrected for FM, these gender differences were still present. After correcting for FM, differences remained between H and L AVF groups for VLDL, TG, VLDL-TG, apo-B, apo-B LDL, apo-B VLDL, apoB/A1 (P <.05). Twenty-four hour integrated GH concentration (IGHC) was inversely related to VLDL, TG, VLDL TG, LDL TG, apoB, apoB VLDL, apoB LDL, Chol/HDL, LDL/HDL, and apoB/A1 in F, but not M (P <.05). Vo(2) peak was directly related to Chol, LDL, HDL(3), and apoB LDL with stronger relationships observed in F. Fasting insulin was related to lipids and lipoproteins in both men and women. These data suggest that, in older adults, elevated levels of AVF, FM, and AVF corrected for FM are associated with unfavorable lipid-lipoprotein profiles and extend similar findings reported in younger males and females with elevated AVF. These data also support previous findings indicating that AVF is a primary determinant of GH release.